Method of treating prostatic hypertrophy with N-acetyl candicidin

ABSTRACT

Orally administered compositions for treating prostatic hypertrophy are described herein, these compositions containing an effective dose of a pharmaceutical formulation containing N-acetyl candicidin. Also, the method of treating prostatic hypertrophy with such compositions, is described herein.

This application is a divisional of copending application Ser. No.313,568 filed Dec. 8, 1972, now U.S. Pat. No. 3,843,785 which is acontinuation of Ser. No. 194,052, filed Oct. 29, 1971, now U.S. Pat. No.3,721,734 which is a divisional of application Ser. No. 70,509, filedSept. 8, 1970, now U.S. Pat. No. 3,714,347 which is a continuation ofapplication Ser. No. 623,847, filed Mar. 17, 1967, now U.S. Pat.3,584,118, which was a continuation-in-part of copending applicationSer. No. 544,712, filed Apr. 25, 1966, now abandoned.

This invention relates to a composition containing a polyenic macrolidecompound and the method of treating prostatic hypertrophy by orallyadministering the same.

It is known that prostatic hypertrophy may in limited cases be treatedby the administration of hormones such as steroids. However, thetreatment with steroids or other hormones is severely restricted sinceits effect is related to the suppression of the secretion of agonadotropic substance by the adrenal cortex. Further, theadministration of a hormone carries with it extensive physiologicaleffects on the organ and organ systems in addition to the prostate.Therefore, there has not been available a composition for the treatmentof prostatic hypertrophy which has a broad spectrum of effectivenessindependent of the cause of the prostatic hypertrophy.

A great number of polyenic macrolide antibiotic compounds are knowntoday which are used or proposed for use as antifungal chemotherapeuticagents and which have been the subject of extensive scientificinvestigation in past years. Biologically, the polyene macrolideantibiotics have been recognized to be potent chemotherapeutic agentsagainst a wide variety of yeasts and fungi. However, the use of thesepolyenic macrolide compounds for the treatment of certain fungalinfections has been limited by their poor oral absorption from thegastrointestinal tract. The application of these polyenic macrolideantibiotic compounds has been restricted primarily to topical use.

It has now been unexpectedly discovered that the oral administration ofcompound, or N-acetyl candicidin a polyenic macrolide compound, has aselective effect on the prostate gland in mammals which does not appearto express its effect by stimulating or suppressing hormonal producingendocrine glands. Its effect on the prostate is carried out by reducingits size and altering its hypertrophic histological picture and textureto that of a normal appearing gland. This effect is believed not due tothe antibiotic function of these polyenic macrolide compounds butapparently to their chemical structure.

Accordingly, one aspect of the present invention is to provide a methodfor the treatment of prostatic hypertrophy which comprises orallyadministering an effective dose of N-acetyl candicidin a specific knownpolyenic macrolide compound.

Another aspect of the present invention is to provide an orallyadministered composition for the treatment of prostatic hypertrophywhich composition comprises a pharmaceutical formulation comprising aneffective dose of a specific known polyenic macrolide compound.

An additional aspect of the present invention is to provide an enterictablet or capsule containing an effective dose of a composition of thepresent invention for the treatment of prostatic hypertrophy.

Other aspects of the invention will be apparent from the followingdetailed description.

According to the present invention, the compositions found effective forthe treatment of prostate hypertrophy in mammals comprise a molecularstructure in which there is attached to a polyenic macrolide nucleushaving at least four conjugated double bonds, at least one hydroxylmoiety (i.e., the well known polyenic macrolide antifungal antibioticcompounds or a composition having a molecular structure in which thereis attached to a polyenic macrolide nucleus at least one hydroxyl groupand at least one moiety selected from the group consisting of aminosugars and N-acyl derivatives thereof, aromatic amines and N-acylderivatives thereof, carboxyls, hydroxy aliphatics, carbonyls, methyls,aliphatics and epoxies). Since the polyenic compounds were firstdiscovered in 1950, a large body of literature has become availabledescribing the extensive chemical investigation of these compounds anddemonstrating that they possess generally similar chemical properties.The present broad classification of the polyenic macrolide compounds isdue to the work of Oroshnik et al, in 1955 (see Polyene Antibiotics,Science, Vol. 121, pp. 147-149). In 1955 only nine glyenic macrolidecompounds had been isolated in reasonably pure form but since then wellover fifty polyenic macrolide compounds have been reported. Undoubtedlysome of these polyenes have been reported more than once under differentnames.

The known polyenic macrolide compounds have been produced as antibioticsby cultivation of Streptomyces in different media and by extraction ofthe substances from these cultures. It has been demonstrated in theliterature that the known polyenic compounds are (1) of fairly highmolecular weight (ca. 700-1500), (2) contain macrocylic lactones, betterknown as macrolides (hereinafter referred to as "polyenic macrolidecompounds"), and (3) each possess a chromophore in the nucleus of fromfour to seven conjugated double bonds (tetraenes, pentaenes, hexaenes,and heptaenes) identified by examination of their ultra-violetabsorption spectra. These conjugated systems are generally unsubstituted(except the methyl pentaenes) and either of the "all-trans" or"cis-trans" configuration. Based on the evidence available to date, itis indicated that the known polyenic macrolide compounds contain a 26 toa 37 membered lactone ring wherein all of the ring atoms except thesingle oxygen atom are carbons. The evidence to date also indicates thatonly C, H, O, and N are present in the known polyenic macrolidecompounds.

The polyenic macrolide nucleus contains a relatively planar lipophilicsection (polyenic chromophore) and a less rigid hydrophilic section dueto the presence of highly polar substituents, particularly hydroxyls, aswell as other substituents which will be discussed in detail laterherein. All of the known polyenic macrolide compounds contain at leastone hydroxyl moiety and in some cases at least six hydroxyl moieties. Itis difficult to estimate the precise number of hydroxyl functionspresent in each known polyene macrolide compound because complete, ornearly complete structures have been proposed for relatively newpolyenes which are: pimaricin [Ceder et al - Acta Chem. Scand., Vol. 18pp 72-125 (1964)]; filipin [Ceder et al - Acta Chem. Scand., Vol. 18, pp558-560 (1964)]; nystatin [Birch et al - Tetrahedron Letters, Vol. 23,pp 1491-1497 (1964)]; lagosin [Dhar et al - J. Chem. Soc., p 842 (1964)]; fungichromin [Cope et al, J. Amer. Chem. Soc., Vol. 84, pp 2170-2178(1962)].

The distinct sections of polar and non-polar character in the polyenicmacrolide nucleus result in the unique and peculiar solubilityproperties exhibited by the polyenic macrolide compounds. As a group ofcompounds the polyene macrolides generally exhibit very poor solubilityin the common organic solvents such as lower alcohols, esters, ketones,ethers, etc., and are insoluble in water. The polyenic macrolidesexhibit improved solubility in mixtures of lipophilic and hydrophilicsolvents, e.g., aqueous solutions of lower alcohols, and are easilysoluble in aqueous pyridine. Good solubility of the polyenic macrolidecompound is noted in highly polar solvents such as dimethyl sulfoxide,formamide, glacial acetic acid, etc.

Any single known polyenic macrolide compound may have substituentslinked to the ring such as amino sugars and N-acyl derivatives thereof,aromatic amines and N-acyl derivatives thereof, carboxyls, methyls,carbonyls, aliphatics, hydroxy aliphatics and epoxies. The majority ofthe polyenic macrolides are amphoteric substances. The acidity of thesepolyenes is due to a carboxyl group and the basicity of the amphotericpolyenes is due to the presence of an amino sugar known as mycosamine(3-amino 3,6 dideoxy-D-mannose), or perosamine (4-amino 4,6dideoxy-D-mannose). The basicity may also be due to the additionalpresence of aromatic amino moieties. Some polyene macrolides such asfilipin, lagosin and fungichromin are neutral. The substitution of theamine function with such organic radicals as acyl groups reduces theeffectiveness of the macrolide nucleus in the treatment of prostatehypertrophy but does not destroy this activity. The acylation results inneutralization of the basic properties and improved solubilities of theN-acylated derivative in various media, such as organic solvents, andreadily permits the formation of water soluble salts, as fully describedin U.S. Pat. No. 3,244,590.

The following articles should be consulted for references to thediscovery, isolation and chemical properties of the polyenic macrolidecompounds:

1. Vining, "The Polyene Antifungal Antibiotics" Hindustan AntibioticsBull., Vol. 3, pp 32-54 (1960).

2. Waksman et al, "The Actinomycetes, Vol. III, Antibiotics ofActinomycetes" (Williams and Wilkins, Baltimore, 1962).

3. Droughet, "Noveaux Antibiotiques Antifongiques" Symp. Int.Chimiotherapie, Naples, 1961, pp 21-50 (1963).

4. W. Oroshnik et al, "Fortschritte der Chemie Organischer Naturstoffe"Vol. XXI, pp 18-79 (1963).

The general class of polyenic macrolide compounds which have beendescribed above and to which the present invention is applicable willnow be discussed in greater detail by reference to the four distinctclasses of polyenic macrolide compounds, that is, tetraenes, pentaenes,hexaenes and heptaenes, and to the substances that fall within each ofthese separate classifications.

The heptaene group of polyene macrolides are classifiable into at leastfive groups which may be correspondingly identified as follows:

A. aromatic I - Identified as those compounds containing the heptaenemacrolide nucleus, one carboxyl group, a single amino sugar moiety(mycosamine) glycosidically linked to the macrolide nucleus and anaromatic amino moiety (p-aminophenyl) aldolically linked to themacrolide nucleus. Representatives of this group are (a) candicidinwhich may possibly be identical to trichomycin A, hamycin (minorcomponent), heptamycin, ascosin and levorin A₂ ; (b) trichomycin B whichmay possibly be identical to levorin A₃, hamycin (major component) andPA-150; and (c) levorin A.

B. Aromatic II - Identified as those compounds containing the heptaenemacrolide nucleus, one carboxyl group, an amino sugar (mycosamine)glycosidically linked to the macrolide nucleus, and an aromatic aminomoiety (N-methyl-p-aminophenyl) aldolically linked to the macrolidenucleus. Representative polyenic macrolides of this group are: (a)candimycin, and (b) hamycin (minor component of hamycin complex).

C. Aromatic III - Identified as those compounds containing the heptaenemacrolide nucleus, an aromatic amino moiety (N-methyl-p-aminophenyl),aldolically linked to the macrolide nucleus, and an amino sugar(perosamine), glycosidically linked to the macrolide nucleus. It isnoted that the aromatic amino moiety just identified has previously beenincorrectly reported in the literature as a p-aminobenzyl moiety.Representative of this group is fungimycin. This substance wasoriginally styled by antibiotic number NC 1968 and for a brief intervalidentified as perimycin and aminomycin.

D. Non-Aromatic - Identified as those compounds containing the heptaenemacrolide nucleus, one carboxyl moiety and a single amino sugar(mycosamine), glycosidically linked to the macrolide nucleus.Representative of this group are: (a) candidin; (b) candidinin; (c)candidoin; (d) amphotericin B; (e) mycoheptin; (f) levorin B; and (g)antibiotic F-17-C.

E. Poorly Defined Heptaenes: A number of heptaene macrolide compoundshave been described in the literature but have not as yet beensufficiently characterized as to all the substituents linked to thepolyenic macrolide nucleus. These heptaene macrolides are Streptomycesabikoensis heptaene, aureofacin, antibiotic 757, ayfactin A, ayfactin B,antifungin 4915, eurotin A, antibiotic AE56, antibiotic 2814-H,grubilin, monicamycin, antibiotics A, B, and C from streptomyces speciesrelated to S. viridans.

It will be understood that where a polyenic macrolide compound of theclass herein described is identical with one of the above namedcompounds, but has been known by another name by reason of independentproduction or production in accompaniment to other antibiotics, theidentification of such substances by the name set forth above isintended to mean the same compound under all other designations.

The N-acyl derivatives of the polyenic macrolide compounds having fourto seven conjugated double bonds useful for the treatment of prostatichypertrophy in accordance with the present invention are generallyprepared by reaction of the corresponding acid anhydride with thepolyenic macrolide substance. In general, the acyl derivatives arederived from monocarboxylic aliphatic acids, dicarboxylic aliphaticacids and aromatic carboxylic acids. Thus the acyl derivatives and theirpharmaceutically acceptable salts, can be defined as derivatives of apolyenic macrolide compound and an organic acid, the acyl group of theacid being linked to at least one amino nitrogen of the macrolidecompound. A detailed description of the preparation of N-acylderivatives of polyenic macrolide compounds may be found, for example,in U.S. Pat. No. 3,244,590.

Examples of the various N-acyl derivatives are formyl, acetyl,propionyl, chloroacetyl (and other halogen - substituted aliphaticmonocarboxylic acids), phenylacetyl, phenoxyacetyl, butyryl, valeryl,caproyl, succinyl, phthalyl, 3-nitrophthalyl, benzoyl, subsitutedbenzoyl and the like.

In the preparation and administration of dosages, a variety ofpharmaceutical formulations may be employed, such as capsules, ortablets, preferably in enteric form. The quantity of effective dosesupplied by each capsule or tablet is relatively unimportant since thetotal dosage can be reached by administration of either one or aplurality of capsules or tablets or both. The capsules employed maycompose any well known pharmaceutically acceptable material, such asgelatin, cellulose derivatives, etc. The tablets may be formulated inaccordance with conventional procedure employing solid carriers,lubricants, etc., well known in the art. Examples of solid carriers are:starch, sugar, bentonite and other commonly used carriers.

The following examples illustrate suitable pharmaceutical formulationscontaining the compounds of this invention.

Example 1

Hard gelatin capsule available from the Robin Pharmacal Corporation(size 00) is filled with about 0.83 grams of lactose (Fast Flowavailable from Foremost Dairies, Inc.) and about 100 mg. of activematerial, the lactose and active ingredient being triturated together ina pestle and mortar until a very fine yellow amorphous powder resulted,prior to filling of the capsule. Obviously, any desired number ofcapsules may be filled by mixing together any amount of lactose andactive ingredient in the same weight ratio indicated above so that eachcapsule will contain 100 mg. active ingredient; and the quantity ofactive ingredient may be altered, as desired, by varying the weightratio of the indicated materials.

Example 2

125 g. of corn starch and 2112.5 g. lactose are dried at 140° F for 12hours before compounding. After drying, each of these materials issifted through a No. 14 mesh stainless steel screen. The sifted cornstarch and lactose are thoroughly mixed for 30 minutes and to thismixture there is added a blended mixture of 250 g. active ingredient and12.5 g. magnesium stearate. This admixture is blended and thencompressed on a tableting machine into 5000 substantially round tabletseach containing 50 mg. active ingredient and weighing about 500 mg.

Example 3

Enteric tablets for use in this invention may be formulated as follows:

16 g. of powdered corn starch (U.S.P. quality) is dried at 120°F for 12hours and passed through a No. 25 mesh stainless steel screen. Thesifted corn starch is then mixed with 255 g. of anhydrous lactose(direct tablet grade). To this mixture, 4 g. of magnesium stearate isadded followed by 50 g. of the active ingredient. These materials arethen mixed in a small pebble mill for 30 minutes and compressed on asingle punch machine producing 1,000 tablets, each containing 50 mg.active ingredient. Each tablet weighs approximately 325 mg. The averagehardness is 6, as measured on a Monsanto Hardness Tester.

The tablets are then placed in a coating pan rotating at 29 r.p.m. andsubjected to warm air of approximately 80°F for about 10 minutes. Then30 cc's of a pharmaceutical glazed composition is applied, thiscomposition being refined wax and rosin free orange flake shellac withanhydrous alcohol as the medium therefor. Talcum (U.S.P.) or similardusting powder is applied to the tablets to prevent the tablets fromsticking to each other or to the pan and this procedure is followedafter the application of each coat to the tablets. The coat is allowedto dry for approximately one hour. Thereafter three additional coats areapplied in a similar manner, each coat comprising 30 cc's of thepharmaceutical glaze, with approximately one hour of drying time betweenthe application of successive coats. After four coats are applied thetablets are dried overnight at room temperature and then four more coatsare applied in the same manner using the same composition. Each coat isallowed to air dry for 3 hours before applying the next coat. Each ofthe 8 coats of the enteric tablets is approximately 0.001 inch inthickness. Obviously, the thickness of the coating can be controlled byvarying the concentration of the pharmaceutical glaze in the alcoholmedium.

The enteric tablets are tested in accordance with the in vitrodisintegration test for enteric-coated tablets described in U.S.P. XVIIand were found to pass this test.

While the number of coats used in the example heretofore described is 8,it will be appreciated that there are many factors to be consideredwhich permit variation in the number of coats, including the size andshape of the tablets or capsules, the type of coat or combination ofcoats, etc.

Other procedures and materials well known in the prior art may beemployed to prepare suitable enteric coatings. The selection of thecoating substance is governed to a large extent by pH and enzymeconsiderations and the desire to have the enteric compositiondisintegrate or dissolve when it reaches the duodenum region of theintestinal tract and not in the stomach. The disintegration ordissolution of an enteric coating in the intestinal tract usuallydepends on several factors, the most important of which are (1) thepresence of acidic groups in the enteric substance which cause it to beinsoluble in the low pH environment of the stomach but soluble in theintestinal tract due to the higher (but usually not alkali) pH of themedia there, and (2) the resistance of the coating to attack by oral andgastric enzymes.

Illustrative of other well known substances that may be used for theenteric coating are the following: cellulose acetate phthalate withresinous carrier; cellulose acetate phthalate-tolu balsam-shellac;cellulose acetate phthalate with fats and waxes; shellac-castor oil;ammoniated shellac; shellac-stearic acid-tolu balsam; stearicacid-castor oil over shellac-silica gel, cellulose acetate phthalateswith or without plasticizer and dusting powder(s); acid phthalates ofglucose, fructose, etc; ternary copolymers of styrene, methacrylic acidand butyl half-ester of maleic acid; alkyd resin-unsaturated fattyacids-shellac; polyvinyl acid phthalate, etc.

For a description of the procedure for manufacturing entericformulations such as those exemplified heretofore, reference should bemade to U.S. Pat. Nos. 2,196,768; 2,433,244; 2,455,790; 2,540,979;2,858,252; 3,080,346 and British Pat. Nos. 760,403 and 820,495.

The effectiveness of the compounds of this invention in treatingprostatic hypertrophy has been confirmed by tests in large mammals,i.e., those weighing at least about 1 kilogram. For example, tests wereconducted on dogs to demonstrate the effectiveness of the polyenicmacrolide compounds in reducing the size of the prostate gland.

In one study, ten dogs were used to determine the action of candicidin,the results of which are reported in Table I below.

Each dog was examined for the gross presence of prostatic hypertrophy bypalpation. All of the dogs, with the exception of two, were at least tenyears of age. The dogs were housed under kennel conditions for a weekprior to the oral administration of candicidin. During theacclimatization period the dogs became adjusted to the feeding andkennel routine. A thorough examination of the dogs, includingelectrocardiography, was undertaken during the acclimatization period.Four of the dogs exhibited a cardiac condition, not unusual for olderdogs, which was confirmed by electrocardiography and subsequently atnecropsy. This cardiac condition did not affect the course of theexperimental trial and indeed was helpful in establishing that even inthe presence of such a condition candicidin may be safely administered.

After the one week acclimatization period, a surgical laparotomy wasperformed on each of the dogs under general anesthesia. The prostategland was measured in three dimensions, lateral, cranial-caudal anddorsal-ventral and was palpated to determine its consistency. Visualobservation of the bladder, intestines, the caudal pole of the kidney,and spleen were made, and the palpation of the liver and kidney wasaccomplished. In all but three of the dogs a punch biopsy of theprostate was taken. The biopsy specimen taken from the left hemisphereof the prostate gland was fixed in formalin for histological andmicroscopic examination. The omission of a prostate in three dogs wasinstituted as a control to determine whether the trauma of taking thebiopsy of the prostrate gland might have some influence on inflammationand size of prostatic tissue. In addition, blood and urine specimenswere taken for candicidin assay and routine examination.

The dogs were permitted to recover from the surgical laparotomyfollowing which each of the dogs was placed on a regimen of oraladministration of candicidin in accordance with the schedule of doseadministration given in Table I below. The drug was administered in ahard gelatin capsule in the animal feed.

                                      TABLE I                                     __________________________________________________________________________                             Animal                                                                            Prostate Size***                                                                             % Decrease                                         Daily   Body     Cranial-  In Gland Size                     Dog         Age  Dosage                                                                             Dose                                                                             Weight                                                                            Lateral                                                                            Caudal                                                                             Dorsal-                                                                            From Initial                      No.                                                                              Procedure                                                                              (years)                                                                            (mg) Days                                                                             (lbs)                                                                             mm   (mm) Ventral                                                                            Volume                            __________________________________________________________________________       1st Laparotomy        53  45   35   40                                     1  2nd Laparotomy                                                                         10-13                                                                              100* 30 40  40   35   40   11.0                                 Autopsy       200* 20 41  42   45   31   7                                    1st Laparotomy        25  20   20   15                                     2  2nd Laparotomy                                                                          4   100* 30 20  17   17   10   51.5                                 Autopsy        0** 20 20  17   19   14   24.5                                 1st Laparotomy        55  26   30   25                                     3  2nd Laparotomy                                                                         13   100* 30 44  26   30   22   12.0                                 Autopsy       400**                                                                              14 36  26   25   25   17.0                                 1st Laparotomy        72  50   50   40                                     4  2nd Laparotomy                                                                         10   100* 30 61  41   39   32   48.8                                 Autopsy       600**                                                                              14 50  35   35   27   77                                5  1st Laparotomy                                                                         17           32  40   40   30   47.0                                 Autopsy       200* 30 20  34   25   30                                     6  1st Laparotomy                                                                         10           39  37   30   28   8.5                                  Autopsy       300* 30 25  34   35   25                                        1st Laparotomy                                                                          8           33  37   26   25   21.0                              7.sup.a                                                                          Autopsy       300* 30 28  27   26   27                                        1st Laparotomy                                                                          15+         30  60   50-55                                                                              45   26.5                              8.sup.a                                                                          Autopsy       300*  5 --  55   45-50                                                                              40                                        1st Laparotomy                                                                         11-13        30  42   42   34   65.0                              9.sup.a                                                                          Autopsy       300* 30 20  30   28   25                                        1st Laparotomy                                                                         10-11        34  35   28   28   67.2                              10 Autopsy       300* 30 25  22   24   17                                     __________________________________________________________________________       *The daily dosage administered after the first laparotomy.                   **The daily dosage administered after the second laparotomy.                  ***The Prostate volume is approximated by multiplying the three              dimensions indicated.                                                          .sup.a No biopsy taken.                                                 

As indicated in Table I a second surgical laparotomy was performed onfour of the ten dogs in lieu of autopsy because these four dogs weresubsequently continued on an altered dose of candicidin to determinewhether increase of the drug dose or discontinuance of dosage wouldfurther affect prostate size. The remaining six dogs were sacrificed andautopsied after completion of the administration of candicidin. The fourdogs on which a second laparotomy was performed were autopsied aftercompletion of the administration of candicidin for the period specifiedin the above table.

At the time of the second laparotomy and at necropsy the prostate glandwas measured and biopsy specimens of the prostate gland of each dog weretaken, with the exception of the three dogs indicated in the table forwhich no biopsy specimens were taken.

In addition, at necropsy, histologic specimens were taken of the generalorgans - prostate, bladder, pancreas, kidney, adrenal, liver, spleen,testes, intestines, caecum, lung, thyroid and heart for furthermicroscopic examination in order to determine whether any toxicreactions had occurred. All tissues taken were formalin fixed andprepared for microscopic examination. The histologic study of the organslisted did not reveal any evidence of drug toxicity.

At necropsy, blood and urine samples were obtained for assay. The assaymethod was essentially the procedure described for the assay ofNystatin-Candicidin in "Assay Methods of Antibiotics" 1955, a laboratorymethod, Donald C. Grove and William D. Randall, pp. 116-119: Method 2.The samples of dog serum and urine investigated microbiologically showedno antifungal activity. The assay tests establish the absence ofcandicidin in the blood and urine of the test animals.

As shown in the above table, the trauma induced by taking of a biopsy ofthe prostate gland was not the cause of the reduction in the size of theprostatic tissue. The gross appearance and measurements of the prostategland taken prior to the administration of candicidin and atlaparotomies performed after the drug has been administered revealed amarked reduction of the size of the prostate gland and normalconsistency of the gland which is consistent with a significantlyyounger age of dog. Microscopic examination of the biopsy specimens ofthe prostate gland on each dog taken at each of the surgical proceduresperformed confirmed the gross observation of normal appearance and asubstantial reduction of size.

The histologic evaluation of the prostate biopsies of dogs taken priorto candicidin administration and at laparotomies did not reveal anycytotoxicity in the gland. The enlarged prostate gland prior to drugadministration is characterized by considerable epithelial tufting orpapillation; cells are tall, columnar with granular cytoplasm, and glandacini are compressed. The marked reduction in the size of the prostategland after candicidin administration is accompanied by a decrease inthe size of the columnar epithelial cells which are mostly cuboidal;diminished or absent granularity; and papillations are reduced orabsent.

As indicated in the above table, body weight loss does not appear to berelated in any quantitive way to the dose of the drug administered sincethe dogs that received 100 mg/day showed a body weight loss no less orgreater than those animals receiving a higher dosage. The data also showthat a short time of administration, as noted with dog No. 8 of arelative high dose, 300 mg daily, for 5 days, effected a significantreduction in size of the prostate gland. In the case of dog No. 2,candicidin administration was discontinued after the second laparotomyas indicated in the table and after an additional 20 days of absence ofdrug administration, it was found that the prostate gland began toincrease in size and had achieved about a 50 percent return towards thevolume noted at the start of the experiment. However, in this dog theprostate gland was not initially pathologically enlarged.

In some of the dogs diarrhea and vomiting occurred upon the oraladministration of candicidin but these effects appeared to be overcomewhen the dogs were fed a supplement of vitamin B-complex andlacto-bacilli.

Similar tests were conducted on dogs using nystatin (a tetraene). Thegross appearance and measurements of the prostate gland taken prior tothe administration of nystatin and at laparotomies performed after thedrug had been administered also revealed a reduction in size of theprostate gland but to a lesser extent than the candicidin treated dogs.

Other tests conducted with polyenic macrolide compounds in mammalsappear to indicate that the larger the chromophore in the macrolidenucleus the more effective is the compound in treating prostatichypertrophy. Accordingly, the heptaene macrolide compounds arepreferably used because they have been found to generally give the bestresults whereas the tetraene macrolide compounds, generally, are leasteffective in reducing the size of the prostate gland.

It is also indicated that cleavage or other alteration of the macrolidenucleus which opens the lactone ring will destroy the activity of thecompounds as will alteration of the chromophore present in the nucleusby total hydrogenation.

Since no one of the substituents found in the polyenic macrolidecompounds such as amino sugars, aromatic amines, carboxyls, carbonyls,methyls, aliphatics, epoxies, etc., occurs in all of the polyenicmacrolide compounds described herein, this suggests that thesesubstituents, except for the hydroxyl function, are not essential forachieving a reduction in the size of the prostate gland, but rather thatthe active structure is the macrolide ring containing a conjugatedchromophore portion (pophilic section) and the flexible hydrophilicportion.

Tests conducted with various polyene macrolide compounds includingfilipin, amphotericin B and fungimycin, indicate that the side chaingroups commonly found in the polyenic macrolide compounds are notessential to activity for treating prostate hypertrophy.

It is preferred, commensurate with the desideratum of obtaining thehighest degree of effectiveness of the compositions of this inventionper given dose of active ingredient, to use an enteric tablet orcapsule. Thus when using a specific known polyene macrolide compound inthe form of an enteric solid, the entire compound will remain intactwhen it reaches the intestinal tract so long as the enteric coatingcomposition retains its integrity in the stomach. On the other hand,administration of the same dose in a standard solid pharmaceuticalformulation may result in a cleavage of any amino sugar present, or ofother groups similarly sensitive to gastric conditions. Such cleavagemay further result in alteration of the polyenic macrolide nucleus,thereby diminishing the effectiveness of the active ingredient.

The effective dosage of the compounds of this invention depends upon theseverity of condition, the stage and the individual characteristics ofeach mammal being treated. It is expected that the compositions willgenerally be administered in a dosage range from about 1 mg to about 100mg active ingredient per kg of body weight per day and preferably fromabout 5 mg to about 40 mg per kg of body weight per day.

What is claimed is:
 1. Process for the treatment of prostatichypertrophy in a large mammal afflicted with prostatic hypertrophy whichcomprises orally administering to said mammal an effective dose fortreating prostatic hypertrophy of a composition comprising N-acetylcandicidin.
 2. Process for the treatment of prostatic hypertrophy asrecited in claim 1, wherein said effective dose comprises from about onemilligram to about 100 milligrams of said N-acetyl candicidin perkilogram of body weight per day.
 3. Process for the treatment ofprostatic hypertrophy as recited in claim 2, wherein said effective dosecomprises from about 5 milligrams to about 40 milligrams per kilogram ofbody weight per day of said N-acetyl candicidin.